U.S. Pat. No. 3,188,313 relates to certain 1-(1-, 2-, and 3-indolylalkyl)piperazines, which are said to have CNS depressant and tranquillising effect.
Other compounds related to the compounds of the invention, which are said to interact with the dopamine and/or the serotonin system, are known in the art.
Thus, EP-B1-496 222, claims compounds having the formula
wherein Ar is a phenyl group, which may be substituted with halogen, alkyl, cyano, hydroxy etc. and Ind is 3-indolyl, which may be substituted with cyano, aminocarbonyl and aminocarbonylamino. The compounds disclosed in EP-B1-496 222 are said to be serotonine antagonists and agonists. It is also mentioned that the compounds have effect on dopamine accumulation in striatum and 5-HTP accumultation in N. Raphe. The compounds are said to be useful as anxiolytica, antidepressiva, neuroleptica and antihypertonica.
WO 99/09025 claims certain 2-(4-aryl-piperazin-1-yl)methyl-1H-indole derivatives. The compounds are said to be dopamine D4 receptor agonists. Further, WO 94/24105 relates to 2-(2-(4-aryl-piperazin-1-yl)ethyl-1H-indole derivatives, which are said to have selective affinity for the dopamine D4 receptor subtype.
EP-B1-354 094 relates to certain oxindoles having the formula
wherein R1 is hydrogen, halogen or alkyl, R2 is hydrogen or alkyl, R3 is hydrogen, alkyl or —S-alkyl and Ar may be chlorophenyl and other substituted aryl groups. The compounds bind to the 5-HT1A receptor and are said to be agonists, partial agonists or antagonists at this receptor. Certain of the compounds are said to possess activity at 5-HT2 receptors.
WO 98/08816 also describes oxindoles, which are said to be psychotropic drugs, and the application contains data showing the activity of certain of the compounds at the D4 receptor.
Pharmazie, 1997, 52, 423–428 describes N-[3-(4-aryl-1-piperazinyl)alkyl] derivatives of indolin-2(1H)-one, quinolin-2(1H)-one and isoquinolin-1(2H)-one and their receptor affinities at the 5-HT1A and the 5-HT2A receptor. The compound 1-(3-(4-phenyl-1-piperazinyl)propyl)indolin-2(1H)-one is described as a 5-HT2A antagonist with weak 5-HT1A agonistic properties. The compound is suggested as a potential antidepressant and/or anxiolytic agent.
Subramamian et al., Heterocyclic Communications 1999, 5, 63–68 describes certain piperazinyl indolyl propanones claimed to show antagonism at dopamine D1/D2 receptors.
Further, Böttcher et al., J. Med. Chem. 1992, 35, 4020–4026, describes certain 3-(1,2,3,6-tetrahydro-1-pyridylalkyl)indoles having dopaminergic activity.
Finally, Pol. J. Pharmacol. Pharm. 1984, 36, 697–703 describes the compound 1-(3-(4-(3-chlorophenyl)-1-piperazinyl)propyl)indane as having serotinolytic properties.
Dopamine D4 receptors belong to the dopamine D2 subfamily of receptors, which is considered to be responsible for the antipsychotic effects of neuroleptics. The side effects of neuroleptic drugs, which primarily exert their effect via antagonism of D2 receptors, are known to be due to D2 receptor antagonism in the striatal regions of the brain. However, dopamine D4 receptors are primarily located in areas of the brain other than striatum, suggesting that antagonists of the dopamine D4 receptor will be devoid of extrapyramidal side effects. This is illustrated by the antipsychotic clozapine, which exerts higher affinity for D4 than D2 receptors, and is lacking extrapyramidal side effects (Van Tol et al. Nature 1991, 350, 610; Hadley Medicinal Research Reviews 1996, 16, 507–526 and Sanner Exp. Opin. Ther. Patents 1998, 8, 383–393).
A number of D4 ligands, which were postulated to be selective D4 receptor antagonists (L-745,879 and U-101958) have been shown to posses antipsychotic potential (Mansbach et al. Psychopharmacology 1998, 135, 194–200). However, recently it has been reported that these compounds are partial D4 receptor agonists in various in vitro efficacy assays (Gazi et al. Br. J. Pharmacol. 1998, 124, 889–896 and Gazi et al. Br. J. Pharmacol. 1999, 128, 613–620). Furthermore, it was shown that clozapine, which is an effective antipsychotic, is a silent antagonist (Gazi et al. Br. J. Pharmacol. 1999, 128, 613–620).
Consequently, D4 ligands, which are partial D4 receptor agonists or antagonists, may have beneficial effects against psychoses.
Dopamine D4 antagonists may also be useful for the treatment of cognitive deficits (Jentsch et al. Psychopharmacology 1999, 142, 78–84.
It has also been suggested that dopamine D4 antagonists may be useful to reduce dyskinesia occurring as a result of the treatment of Parkinson's disease with L-dopa (Tahar et al. Eur. J. Pharmacol. 2000, 399, 183–186).
Dopamine D3 receptors also belong to the dopamine D2 subfamily of receptors, and they are preferentially located in limbic regions of the brain (Sokoloff et al. Nature 1990, 347, 146–151), such as the nucleus accumbens, where dopamine receptor blockade has been associated with antipsychotic activity (Willner Int. Clinical Psychopharmacology 1997, 12, 297–308). Furthermore, an elevation of the level of D3 receptors in the limbic part of schizophrenic brains has been reported (Gurevich et al. Arch. Gen. Psychiatry 1997, 54, 225–32). Therefore, D3 receptor antagonists may offer the potential for an effective antipsychotic therapy, free of the extrapyramidal side effects of the classical antipsychotic drugs, which primarily exert their effect by blockade of D2 receptors (Shafer et al. Psychopharmacology 1998, 135, 1–16; Schwartz et al. Brain Research Reviews 2000, 31, 277–287).
Moreover, D3 receptor blockade results in a slight stimulation in the prefrontal cortex (Merchant et al. Cerebral Cortex 1996, 6, 561–570), which could be beneficial against negative symptoms and cognitive deficits associated with schizophrenia. In addition, dopamine D3 antagonists can reverse D2 antagonist-induced EPS (Millan et al. Eur. J. Pharmacol. 1997, 321, R7–R9) and do not cause changes in prolactin (Reavill et al. J. Pharmacol. Exp. Ther. 2000, 294, 1154–1165). Consequently, D3 antagonistic properties of an antipsychotic drug could reduce the negative symptoms and cognitive deficits and result in an improved side effect profile with respect to EPS and hormonal changes.
Dopamine D3 agonists have also been considered relevant in the treatment of schizophrenia (Wustow et al. Current Pharmaceutical Design 1997, 3, 391–404).
According to the present invention, a novel class of dopamine D4 receptor ligands is provided. Most of the compounds of the invention also have high affinity for the dopamine D3 receptor and as mentioned above, dopamine D3 antagonistic properties of an antipsychotic drug may reduce the negative symptoms and cognitive deficits of schizophrenia and result in an improved side effect profile.
Moreover, certain of the compounds of the invention have the further advantage of having only very weak effect at adrenergic alpha-1-receptors which imply a low propensity to cause orthostatic hypotension.